
Zoila Areli Lopez Bujanda
Despite the profound and durable clinical responses to checkpoint therapy that have led to FDA approval for PD1 and CTLA4 blockade in several tumor types, patients with prostate cancer have yet to benefit from these therapies. Understanding the immunosuppressive pathways underpinning the lack of anti-tumor responses in prostate cancer, as well as the mechanisms that regulate these pathways, may lead to novel treatment paradigms that unleash the potential of checkpoint therapy in the treatment of prostate cancer.
As a Ph.D. student in Charles Drake’s laboratory, I found that an important immune-resistance mechanism is initiated as a byproduct of the main line of treatment for prostate cancer, androgen deprivation therapy (ADT). Androgen receptor loss of signaling following ADT induces prostate tumor cells to upregulate the expression of IL-8. IL-8 is a chemokine that recruits suppressive neutrophils in the context of cancer known as polymorphonuclear myeloid derived suppressor cells (PMN-MDSCs). Inhibiting IL-8 signaling led to a reduced recruitment of PMN-MDSCs to prostate tumors. Furthermore, hindering the recruitment of PMN-MDSCs in combination with checkpoint blockade significantly delayed tumor outgrowth. Our data provide a rationale for targeting PMN-MDSC recruitment in combination with immune checkpoint blockade for the treatment of prostate cancer before ADT is administrated, when the immune-suppressive microenvironment has not been yet established. Based on these findings, our group has launched an investigator-initiated clinical trial to evaluate targeting PMN-MDSCs in combination with checkpoint blockade before ADT in prostate cancer patients.